Alzheimer's disease is a fatal neurodegenerative disorder currently affecting more than 20 million people worldwide and with increasing rates of occurrence. It is estimated that the incidence rate will double over the next 30 years making Alzheimer's disease a leading cause of mortality among the elderly (van Leeuwen et al., Neurobiology of Aging, 2000, 21: 879-891). Characteristics include declination of intellectual functions (memory, language, visiospatial skills and problem solving skills) and decreased abstract reasoning along with abnormal behaviors. Alzheimer's disease results in eventual loss of motor function, inanition and death (Friedlander et al., Clinical Practice 2006, 137: 1240-1251). Alzheimer's disease generally occurs later in life and is said to be of “late-onset.” The prevalence of Alzheimer's disease in people aged 65-74 years is 3%, while prevalence in age groups 75-84 years and 85 years and older are 19% and 47%, respectively (Friedlander et al., 2006). The average lifespan of an individual diagnosed with Alzheimer's disease is 8-10 years following onset (Friedlander et al., 2006).
As a precursor to being diagnosed with Alzheimer's disease, many first experience amnesic mild cognitive impairment (MCI), which is thought to be a transition stage between normal aging and Alzheimer's disease or a preclinical stage of Alzheimer's disease (Arch Neurol. 2004 January; 61(1):59-66). When memory loss is the predominant feature, this type of impairment is referred to as amnesic MCI and is likely to convert to Alzheimer's disease over time as cognitive decline increases.
Alzheimer's disease is grouped into seven stages, each more debilitating than the last. The first stage is characterized by retrospective analysis once symptoms of Alzheimer's disease have progressed leading to the final stage consisting of dementia and severe cognitive function declination often requiring fulltime home care for the patient (Friedlander et al., 2006) resulting in enormous health care expenditures.
Alzheimer's disease incidence appears to correlate with certain risk factors. These risk factors include head trauma, ethnicity, high-calorie high-fat low-folate diet, limited education, hypercholesterolemia, diabetes mellitus and a sedentary lifestyle. An autosomal dominant inheritance pattern is observed in about 5% of cases which display familial incidence (Friedlander et al., 2006).
The exact cause of Alzheimer's disease is not currently known, however, the disease is regulated by many pathways in an extremely complicated fashion. Pathways include defective metabolism of beta-amyloid protein (Aβ), abnormal neurotransmission (glutamine, andrenergic, serotonin and dopamine), inflammation, hormonal and oxidative pathways (Frank et al., Ann. Clin. Psychiatry 2005, 17(4): 269-286). Four genes appear to be involved in Alzheimer's disease. These genes encode the amyloid precursor protein (APP), presenilin 1, presenilin 2 and apolipoprotein E (Frank et al., 2005). Alzheimer's disease can be characterized in regions of the brain due to the presence of fibrillary plaques or tangles. Plaques are extracellular deposits and tangles observed intracellularly. Plaques contain Aβ and its fragments Aβ40 and Aβ42 while tangles contain the microtubule-associated protein known as tau (Frank et al., 2005). The Aβ fragments are the products of an abnormal proteolytic cleavage event involving APP (the precursor). Plaques may form in areas of the brain involved in memory formation and information acquisition. N-methyl-D-aspartate (NMDA) receptors are believed to be involved with the neurotoxic events of Alzheimer's disease and Aβ may be directly involved. Tangles are created when tau protein aggregate together after being hyperphosphorylated at specific sites by proteins kinases. In particular, the protein kinase glycogen synthase kinase-3 beta (GSK-3β) has been implicated in the hypersphorylation of tau (Proc Natl Acad Sci USA. 2005 May 10; 102(19):6990-5), leading to tangle formation and axonal microtubule break down. Aβ has been shown to stimulate GSK-3β activity within neurons (Neuroscience 2002; 115(1):201-11). The break down of microtubules prevents axonal transport, leads to the loss of synapses, and neurodegeneration.
Common methods of treatment regarding cognitive and functional decline include cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. Events of psychoses and agitation may be treated with atypical antipsychotics (such as Olanzapine and Risperidone) and mood stabilizers. Finally, depression and anxiety may be treated with selective serotonin reuptake inhibitors, tricyclic antidepressants, norepinephrine reuptake inhibitors and central α2-adrenergic autoreceptor and heterorecptor antagonists (Friedlander et al., 2006).
In the general population, Alzheimer's disease strikes the majority of patients at a relatively late age, but for those with Down syndrome (also known as “trisomy 21” or “DS”), the disease is more rapid. Most people with Down syndrome develop Alzheimer's pathology by late middle age, including deposits of the plaque-forming protein Aβ that are often more severe than in most other Alzheimer's patients.